Phase separation of nuclear tau and its role in gene regulation

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Project summary Tau is a microtubule-associated protein found in neurofibrillary tangles in the brains of Alzheimer’s disease patients. Tau can form amyloid fibrils both in vitro and in vivo and can undergo liquid-liquid phase separation in the presence of crowding agents and nucleic acids. While much of tau research has focused on its microtubule associated functions and aberrant aggregation in the context of Alzheimer’s disease, tau is also found in the nucleus. Mounting evidence has suggested that nuclear tau might play a role in DNA protection, chromosome stability, and heterochromatin formation although the molecular mechanisms behind these functions have largely remained enigmatic. Tau’s presence in heterochromatin is especially intriguing, since it localizes to an environment where it would be predicted to phase separate, with other proteins known to do so. Therefore, in this exploratory proposal, we aim to test a hypothesis that tau might play a role in heterochromatin regulation through a phase separation mechanism. We also hypothesize that aberrant phosphorylation and disease- relevant mutations may disrupt this process and may lead to compromised cellular ability to regulate gene expression. We propose to test these hypotheses through in vitro biophysical and structural assays, coupled with cell-based experiments designed to gain better understanding of the potential functions and biophysical properties of nuclear tau. We aim to provide a new viewpoint regarding the molecular mechanisms behind Alzheimer’s disease that is distinct from the amyloid hypothesis and hope to inform the development of new therapeutic and diagnostic approaches.